Bacterial infections remain one of the major threats to human lives. As bacterial resistance to even the most potent antibiotics increases, so too must the efforts to identify novel anti-bacterial strategies. Among other virulence factors, many pathogenic bacteria secrete toxins that kill eukaryotic cells by disturbing their plasma membrane. Bacterial pore-forming toxins are active on the cell surface, causing pore formation and disruption of the plasma membrane followed by either lysis or apoptosis of host target cells, whereas bacterial phospholipases induce the death of host cells by enzymatic degradation of plasmalemmal phospholipids.
Bacterial membrane-destabilizing toxins, such as cholesterol-dependent cytolysins (CDCs: pneumolysin O, streptolysin O, tetanolysin), α-hemolysin or bacterial phospholipases (phospholipase C, sphingomyelinase) play a critical role in the establishment and progression of infectious diseases. Such diseases are pneumonia, a major cause of death among all age groups and the leading cause of death in children in low income countries; bacteremia, a severe complication of infections or surgery, which is characterized by high mortality due to sepsis and septic shock; and meningitis, a life-threatening disease, which also leads to serious long-term consequences such as deafness, epilepsy, hydrocephalus and cognitive deficits.
To target host cells bacterial membrane-destabilizing toxins either bind to individual membrane lipids (lipid head groups) or exploit the non-homogenous nature of the lipid bilayer of eukaryotic cells' plasma membrane, interacting with microdomains enriched in certain lipid species (Gonzales M. R. et al., Cell. Mol. Life Sci. 2008, 65:493-507). The non-homogenous distribution of lipids within the bilayer is not favored by in vivo conditions since transmembrane proteins and the presence of a multitude of individual lipid species with variable lengths and saturation status of their acyl chain oppose lipid de-mixing and thus the formation of stable lipid microdomains (Simons K. and Gerl M. J., Nat. Rev. Mol. Cell Biol. 2010, 11:688-99). However, lipid de-mixing can be taken to its extremes in artificial protein-free liposomes, manufactured from a limited number of carefully selected lipid species, where extended, stable lipid microdomains can be created (Klose C. et al., J. Biol. Chem. 2010, 285:30224-32). Moreover, artificial liposomes allow for much higher relative concentrations of a particular lipid than those ever likely to occur in vivo. Therefore, liposomes displaying stable lipid microdomains of defined biochemical properties and possessing high relative concentrations of particular lipids can be produced. Liposomes are currently used in the cosmetic and pharmaceutical industries as carriers for topical and systemic drug delivery and are considered to be non-toxic.